Several aminosterol compositions have been isolated from the liver of the dogfish shark, Squalus acanthias. One such aminosterol is squalamine (3β-(N-[3-aminopropyl]-1,4-butanediamine)-7α, 24R-dihydroxy-5α-cholestane-24-sulfate), the chemical structure of which is shown in FIG. 1. This aminosterol, which includes a sulfate group at the C-24 position, is the subject of U.S. Pat. No. 5,192,756 to Zasloff et al., which describes squalamine's antibiotic properties.
Since its discovery, however, several other interesting properties of squalamine have been revealed. Most notably, as described in U.S. Pat. No. 5,792,635 (issued Aug. 11, 1998) and U.S. Pat. No. 5,721,226 (issued Feb. 24, 1998), which are incorporated in their entirety by reference, squalamine may inhibit the growth of endothelial cells and therefore function as an antiangiogenic agent. The use of squalamine as an antiangiogenic agent for the treatment of neovascularization in the eye and for the treatment of cancers is disclosed in U.S. patent application Ser. No. 09/985,417 (filed Nov. 24, 1998) and U.S. Pat. No. 6,147,060 (issued Nov. 14, 2000) and U.S. Pat. No. 6,596,712 (issued Jul. 22, 2003) which are also incorporated in their entirety by reference.
Methods for synthesizing squalamine have been described in, for example, U.S. Pat. No. 6,262,283 (issued Jul. 17, 2001), U.S. Pat. No. 6,610,866 (issued Aug. 26, 2003), U.S. Pat. No. 5,792,635 (issued Aug. 11, 1998) and in U.S. patent application Ser. No. 10/268,660. These U.S. patents and patent applications are incorporated in their entirety by reference.
Although squalamine has been previously reported to inhibit the proliferation of endothelial cells and therefore found to be useful as an angiogenesis inhibitor, a need still exists for forms of squalamine that can be readily administered to patients, especially in the form of therapeutically active, soluble salts that exhibit thermal stability upon storage and minimal toxicity and for economical methods for the manufacture of these salts. Accordingly, the identification of salts of squalamine which satisfy these requirements and which specifically inhibit angiogenesis, is an object of this invention.